Research on drug-eluting beads, reported in a satellite symposium at February’s EAHP congress in Maastricht, suggests roles for doxorubicin- and irinotecan-loaded beads
Laurence A Goldberg
Pre-transplantation targeted chemoembolisation of hepatocellular carcinomas using doxorubicin-loaded drug-eluting beads is associated with improved anti-tumour activity compared with conventional chemoembolisation, according to Pierre Goffette (professor of interventional radiology, Saint-Luc University Clinics, Catholic University of Louvain, Belgium).
Transarterial chemoembolisation (TACE) – in which a chemotherapeutic agent is injected into the hepatic artery along with an embolising agent – can be useful in managing the subgroup of people with hepatocellular carcinomas (HCCs) who are candidates for liver transplantation and also for some with advanced or multinodular disease who are unsuitable for curative treatment, Professor Goffette explained. The rationale for the procedure is that HCCs receive 90–100% of their blood supply via the hepatic artery, whereas normal liver tissue receives the majority (75–80%) of its blood supply via the portal vein.
Studies showed that TACE was superior to transarterial embolisation (TAE) or conservative treatment. Survival at one and two years was improved, although benefits were lost after three years and chemoembolisation became the standard approach for a selected group of candidates with intermediate unresectable HCC, Professor Goffette said.
The possibility of chemoembolisation for patients awaiting liver transplants was considered next. This group of patients has a large dropout rate due to excess tumour growth and extrahepatic spread of the tumour. The thinking was that TACE could be used to control tumour growth if a wait of longer than six months was needed. It might also be used to achieve downstaging of the tumour to fit the Milan staging criteria for a successful liver transplant (no evidence of extrahepatic tumour and unifocal tumour mass of less than 5 cm in diameter or fewer than four multifocal tumours, each less than 3 cm in diameter).
Studies show that patients who respond to TACE have better post-transplant survival than nonresponders. However, a complete response occurs in fewer than 10% of patients and two-year survival is about 40% – and this prompted researchers to look for more effective measures, Professor Goffette explained.
Drug-eluting beads (DEBs; DC Beads®) are hydrogel microspheres that are biocompatible, hydrophilic and nonresorbable. They can be loaded with suitable chemotherapeutic agents and provide controlled release of the drug in the tumour bed. The advantage is that they provide a sustained high level of drug in the tumour but a low level in the systemic circulation, he said. In practice these advantages translate into better results – one study showed that DEB-TACE was associated with a response rate of 75% at six months and a two-year survival of 89%.
In Professor Goffette’s department 67 patients have now been treated with DEBs. Of these, 16 were candidates for liver transplant but seven originally fell outside the Milan criteria. The treatment comprises 4 ml (two vials) of 300–500 µm particles loaded with 25 mg/ml doxorubicin (giving a total dose of 100 mg doxorubicin). This is mixed with 4 ml of an iodine-based contrast medium. The treatment protocol allows for additional unloaded microspheres to be given if flow persists in tumour vessels and for treatment to be repeated up to four times at three-monthly intervals.
The results show that patients receive an average of 2.7 treatments. Complete responses were seen in four patients and partial responses in 11; there was significant downstaging in seven. Ten patients have received liver transplants, four are waiting and two have died. When the transplant is performed there can be difficulties in creating arterial and biliary anastamoses, but these are known doxorubicin-related problems, Professor Goffette noted.
In summary, Professor Goffette said pre-transplantation DEBs-TACE provides effective antitumour treatment and that tumour recurrence on the graft is not seen if near-complete HCC necrosis is achieved preoperatively. As TACE-induced surgical complications are mainly due to doxorubicin they could perhaps be avoided by using cisplatin instead, he suggested. Asked why 100 mg dose of doxorubicin was used in preference to the usual 50–70 mg dose, Professor Goffette explained that due to the technique’s precision a larger dose could be used – although it might contribute to complications.
Stability of doxorubicin-loaded beads
DC Beads® can be loaded with doxorubicin and stored for 14 days at 2–8°C. This means DC Beads® could be loaded with doxorubicin in advance and added to the range of drugs prepared by a centralised intravenous additive service, Jean-Daniel Hecq (chief pharmacist, UCL de Mont-Godinne, Yvoir, Belgium) told the audience.
The stability of doxorubicin in solution is well described and can be up to 124 days in some conditions. The stability of doxorubicin in DC Beads was tested using doxorubicin injection solutions from several different manufacturers. The bead diameters were 500–700 µm, and a 12-hour loading time was allowed. After nil, seven and 14 days doxorubicin was eluted from the beads and measured by HPLC. The results showed that there had been no loss of drug and it was elutable from the beads.
There are two issues to consider when using drug-eluting beads: first, whether the cytotoxic agent is effective in the cancer target to be treated, and second, whether the drug can both be loaded onto and eluted from the beads, said Irene Krämer (pharmacy director, Johannes Gutenberg University Hospital, Mainz, Germany).
The “beads” are polyvinyl alcohol (PVA) hydrogel microspheres that contain a high proportion of 2-acrylamido-2-methylpropanesulfonate (AMPS), which provides large numbers of negatively charged sulphonate (SO3–) groups. The spheres can be loaded with negatively-charged drugs, which bind to the sulphonate groups and are then released again once injected. Suitable drugs include the anthracycline glycosides, doxorubicin and epirubucin and the topo-isomerase I inhibitors irinotecan and topotecan, Professor Krämer said.
The beads are supplied in vials containing 2 ml of microspheres (DC Beads) in 6 ml of buffered saline. DC Beads are tinted blue for easy visualisation and are available in four different diameters. The bead diameter is selected according to the size of vessels to be embolised.
Irinotecan is used to treat metastatic colorectal cancer and hepatocellular cancer. It is usually given in a dose of 200–400 mg and comes in vials containing 100 mg. Irinotecan is loaded onto DC Beads in a concentration of 50 mg/ml (equivalent to 100 mg per vial). The loading process involves withdrawal of as much of the saline packing solution as possible, followed by addition of the drug solution. The mixture is then left to equilibrate. The loading time is two hours and for irinotecan this is independent of the bead size. Once loaded with irinotecan the blue-tinted beads become turquoise.
The stability of the loaded beads has been investigated in Professor Krämer’s department. All studies were performed using the Campto® (Pfizer) brand of irinotecan. Irinotecan itself is known to be stable in solution provided it is protected from light, which causes degradation photolysis. Studies showed that 95% of the initial dose was loaded onto the beads and this remained constant for 28 days at room temperature. Further studies were performed to determine whether the drug had been degraded and was elutable from the beads. The results confirmed that after 28 days more than 90% of the drug had not been degraded and was elutable. In normal clinical practice the beads are mixed with a contrast medium so that cannula placement can be checked radiologically. For this reason, a third study was undertaken in which the drug-loaded beads were mixed with a non-ionic contrast medium (Accupaque®) and stored in 20 ml syringes, protected from light in a refrigerator. There was a small initial reduction in the amount of drug loaded onto the beads which was presumed to be due to diffusion. Thereafter the levels remained constant (more than 86%) for the next 13 days.
Irinotecan-loaded DC Beads are chemically stable for a period of 28 days when stored light-protected at room temperature and the drug is elutable. Moreover, the loaded beads can be mixed with nonionic contrast medium in a ready-to-use form and be stored for 13 days in a fridge, Professor Krämer concluded. Future studies will examine the stability of the mixture over a 28-day period and studies with topotecan will also be started, she added.
Medicine or device?
The question of whether drug-eluting beads should be classified as medical devices or drugs still perplexes pharmacists and could have important implications for the handling of the product, according to Ron Pate (department of medicines management, Keele University, UK). Although pharmacists think of the product as being a medicine, according to current definitions it should be considered a device, he explained.
In the EU a medicine is defined as: “Any substance or combination of substances presented for treating or preventing disease in humans” and/or “with a view to making a diagnosis, restoring, correcting or modifying physiological functions”. A medical device is defined as: “Any instrument, apparatus, appliance, material or other article, used alone or in combination, including the software necessary for its proper application.” It is to be used on humans for:
- Diagnosis, prevention, monitoring, treatment or alleviation of disease.
- Diagnosis, prevention, monitoring, treatment or alleviation of or compensation for an injury or handicap.
- Investigation, replacement or modification of the anatomy or of a physiological process.
- Control of conception.
Additionally, it “does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but . . . may be assisted in its function by such means.”
Devices are further classified as low, medium or high-risk products. Medium-risk products include elastomeric pumps and unloaded beads, whereas drug-eluting stents and “precision beads” (that is, drug-loaded beads) fall into the high-risk category.
One way forward might be to have a new category of combination products, Mr Pate suggested. For example, the FDA defines a combination product as “a product comprising two or more regulated components, ie drug/device, drug/biologic, or drug/device/biologic, that are physically, chemically or otherwise combined or mixed and produced as a single entity”. This includes a device coated or impregnated with a drug or biological such as a drug-eluting stent or a catheter with an antimicrobial coating. Other definitions include “two or more separate products, eg drug and device, in a single package” and “drug, device or biological packaged separately; where both are required to achieve intended use”.
However, both the FDA and the CE marking scheme determine the nature of a product according to its primary mode of action. For example, a stent’s primary mode of action is to open a blood vessel by mechanical action; drug elution is secondary, Mr Pate noted. The DC Bead is a drug-delivery embolisation system that is supplied without doxorubicin, he pointed out. It is CE-marked for its intended use thus: DC Bead is intended to be loaded with doxorubicin for the purpose of:
- Embolisation of vessels supplying malignant hypervascularised tumour(s).
- Delivery of a local, controlled, sustained dose of doxorubicin to the tumour(s).
According to current definitions DEBs are devices – but this raises many questions. For instance, should loading with doxorubicin change the status of the product? Who should purchase, supply and prepare DC Beads®? Who is responsible for their use? Are specialist techniques or skills needed for preparation? What information is needed about product stability? What about product liability? ■